tbuckley/cabot-search huggingface dataset:
MODL-39. CHARACTERIZING NON-ENHANCING TUMOR USING MULTI-SHELL DIFFUSION MRI
Authors: Ehsan Golkar, Drew Parker, Steven Brem, Ragini Verma
Journal: Neuro-Oncology (2022)

Abstract Characterizing infiltration in the non-enhancing tumor (NET) is clinically crucial as infiltration leads to progression, and a reduction in survival times. As voxel-wise biopsy of these regions is infeasible, a non-invasive MRI-based identification of infiltration would be a significant contribution. Diffusion MRI (dMRI), with its ability to model different levels of water restriction, as is caused by infiltration and edema, is well positioned to model the NET. This is achieved via multicomparment modeling (MCM) of the dMRI where infiltration, vasogenic edema and healthy tissue (with complex fibers) form the different compartments. Current MCM approaches are either not designed for NET or rely on advanced MRI scans currently not feasible in the clinic. The simplest ball-tensor models, including Hoy 2014 using multi-shell data and FERNET 2020 for single-shell data, consists of a free water compartment that models vasogenic edema and a tensor modeling underlying tissue. These single-tensor methods cannot model complex WM fibers. Our proposed model consists of two steps. First, two bundles are fit: an isotropic bundle with two balls that model isotropic free diffusivity and restricted diffusivity, and a bundle containing stick and zeppelin, corresponding to intra-cellular and extra-cellular diffusion of axons, respectively. Next, a fiber orientation distribution (FOD) is estimated from the fitted parameters. We applied our modeling to multi-shell data from eight patients with glioblastoma, and one patient with a metastatic brain tumor. Our method produces maps corresponding to free water (CSF), restricted diffusion, intra-cellular, and extra-cellular volume fractions. Preliminary results show that restricted diffusivity map of NET comprises 46% of vasogenic metastatic edema compare to 15% of infiltrated GBM edema. In conclusion, we demonstrate that our proposed model shows promise to characterize the NET region of various brain tumors, and distinguishing tumor types. These compartments will provide invaluable radiomic features that no other modality can capture.
CTIM-25. NEOADJUVANT ANTI-PD1 IMMUNOTHERAPY FOR SURGICALLY ACCESSIBLE RECURRENT GLIOBLASTOMA: CLINICAL AND MOLECULAR OUTCOMES OF A STAGE 2 SINGLE-ARM EXPANSION COHORT
Authors: J Ricardo McFaline-Figueroa, Robert Prins, Yu Qiao, Lu Sun, Gang Li, Jiyoon Kim, Eudocia Lee, Lakshmi Nayak, Ugonma Chukwueke, Rameen Beroukhim, Tracy Batchelor, E Antonio Chiocca, Lisa Doherty, Jennifer Stefanik, Kathryn Partridge, Amanda Spearman, Maria Lavallee, Alexa Myers, Corey Laforest-Roys, Rachel Fox Garcia, Wenya Linda Bi, Omar Arnaout, Pierpaolo Peruzzi, G Rees Cosgrove, Keith Ligon, Isabel Arrillaga-Romany, Jennifer Clarke, David A Reardon, Timothy Cloughesy, Patrick Y Wen
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma is immunologically “cold”, with little clinical response to single-agent immune-checkpoint inhibitors (ICI). Our previous randomized study of neoadjuvant and adjuvant pembrolizumab versus adjuvant pembrolizumab in recurrent glioblastoma identified a molecular signature for ICI and suggested that neoadjuvant pembrolizumab improved survival (PMID30742122). We extended these original findings with a single-arm expansion cohort of glioblastoma patients at first or second relapse undergoing surgical resection for recurrent disease. Eligibility was identical to the original study. Patients receiving &amp;gt; 4mg dexamethasone, or with prior immunotherapy or anti-angiogenic therapy were excluded. The primary objective was to determine the effect of neoadjuvant pembrolizumab on cell cycle/cancer proliferation genes. Secondary objectives were PFS-6 and OS. Twenty-five patients received neoadjuvant pembrolizumab followed by tumor resection and adjuvant pembrolizumab until progression or unacceptable toxicity. The median age of participants was 60 years and median KPS was 90. Ninety-six percent of tumors were IDH wild-type and 48% were MGMT promoter methylated. Neoadjuvant pembrolizumab continued to induce alterations in the tumor microenvironment (T-cell/IFN upregulation, cell cycle downregulation; molecular responders (MR)), but the proportion of MR in this trial was 36% compared with 70% in the original treatment cohort. Median OS was 6.8 months. There were no CTCAE grade 4-5 AEs attributable to pembrolizumab. Further analysis of prognostic differences between stage 1 and 2 subjects is underway, as are additional immune and genotypic correlates to further define molecular changes induced by pembrolizumab. Anti-PD1 monotherapy triggers an intra-tumoral genetic signature associated with interferon-γ response and suppression of cell cycle/cancer proliferation in recurrent glioblastoma, though does not extend OS. This surgical window-of-opportunity paradigm allows for attribution of molecular effects to single agents. Future work will evaluate the differences in patient population, tumor characteristics, and address additional immune checkpoints and/or signaling pathways that can be targeted to augment the effectiveness of anti-PD1 in glioblastoma.
CTNI-41. TRANSITION OF LONG-TERM TREATMENT RESULTS OF 493 CASES OF NEWLY DIAGNOSED GLIOBLASTOMA AND SURVIVAL BENEFIT BY COMBINATION WITH PDT AND AFTV - AIMING TO ESTABLISH NEW STANDARD TREATMENT
Authors: Masayuki Nitta, Yoshihiro Muragaki, Taiichi Saito, Shunsuke Tsuzuki, Shunichi Koriyama, Atsushi Kuwano, Soko Ikuta, Takakazu Kawamata
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method. METHODS The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated. RESULTS The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age ( p &amp;lt; 0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Investigator-led clinical trial. CONCLUSION The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.
INNV-09. IMPACT OF MOLECULAR MARKERS ON TREATMENT OUTCOME OF GLIOBLASTOMA PATIENTS TREATED WITH CONCURRENT TUMOR-TREATING FIELDS (TTF) AND CHEMORADIATION: SECONDARY ANALYSIS OF SPARE TRIAL
Authors: Louis Cappelli, Allison Kayne, Spencer Poiset, Muneeb Niazi, Ayesha Ali, Iyad Alnahhas, Wenyin Shi
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES SPARE trial (Scalp-sparing radiation with concurrent temozolomide and tumor treating fields; NCT03477110) is a single-arm pilot study that evaluated the safety and feasibility of concurrent TTF with chemoradiation for adult patients with newly diagnosed GBM. The current study is a secondary analysis evaluating the impact of molecular markers (PTEN, TP53, EGFR, and TERT) on overall survival (OS) and progression-free survival (PFS) of the patients in the trial. METHODS Molecular markers of histologically-confirmed, IDH-wildtype GBM patients age ≥ 18 years old with a KPS ≥ 60 who received concurrent chemoradiation and TTF followed by maintenance TMZ + TTF were evaluated. Molecular profile was evaluated with next-generation sequencing. Impact of mutations in PTEN, TP53, EGFR, and TERT on OS and PFS was evaluated using a multivariable backward model. RESULTS A total of 30 patients were enrolled in the SPARE trial, and 1 patient with IDH-mutant was excluded from the current analysis. All patients underwent concurrent TTF and chemoradiation. The median age is 58 and KPS was 90. 9 patients had methylated MGMT promotor. 14 patients were found to have PTEN mutation, 9 patients with EGFR, 7 with TP53 mutation, and 23 patients with TERT mutated. MGMT methylation remained statistically significant for an increased OS (p=0.032; HR 7.18). TERT mutation had a statistically significant improvement in PFS (P=0.003) and OS (p=0.012). However, neither EGFR, TP53, nor PTEN showed any association of PFS or OS for patients who received concurrent TTF and CRT. CONCLUSIONS In this secondary analysis, patients with MGMT methylation showed better PFS and OS as expected. Neither EGRF, TP53, or PTEN mutation showed any association with PFS or OS. Patients with TERT mutant showed improved OS of patients treated with concurrent TTF with chemoradiation. A TERT mutation may be a new molecular biomarker in the described treatment approach.
PATH-31. ECDNA PROMOTES TUMORIGENICITY AND INTRATUMORAL HETEROGENEITY IN MEDULLOBLASTOMA
Authors: Owen Chapman, Sunita Sridhar, Shanqing Wang, Jill Mesirov, Lukas Chavez
Journal: Neuro-Oncology (2022)

Abstract Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common pediatric brain tumor. To assess the clinical importance of ecDNA in MB, we applied computational methods to detect ecDNA in the genomes of a cohort of 468 MB patients and 31 MB model systems. Among patients, ecDNA was detected in 18% of tumors and carried over twofold greater risk of mortality. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. Between sequential patient biopsies at initial diagnosis and subsequent relapse, we observed structural variation at ecDNA loci and generation of new ecDNA sequences. Among model systems, ecDNA was found in 19 of 31 genomes (61%). Although ecDNA was far more prevalent among MB models than patients, the ecDNA genomic sequences were conserved between most patient-derived xenograft (PDX) models and the human tumors from which they were made. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identified regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we conducted an in vitro CRISPRi screen targeting regulatory regions on the ecDNA of a MB cell line and identified distal enhancers which promote proliferation. Using single-cell sequencing, we have also developed methods to explore intratumoral heterogeneity of ecDNA in a p53-mutant SHH MB patient tumor and its corresponding PDX model. In summary, our study analyzes the frequency, diversity, and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches.
DDDR-06. NEUROFIBROMATOSIS TUMOR SUPPRESSORS COOPERATIVELY DRIVE TUMOR DE-DIFFERENTIATION AND MEK INHIBITOR RESISTANCE IN PERIPHERAL NERVOUS SYSTEM TUMORS
Authors: Harish Vasudevan, Emily Payne, Cyrille Delley, Matthew Sale, S John Liu, Sydney Lastella, Calixto-Hope Lucas, Charlotte Eaton, Tim Casey-Clyde, Stephen Magill, William Chen, Alyssa Reddy, Steve Braunstein, Arie Perry, Line Jacques, Melike Pekmezci, Adam Abate, Frank McCormick, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract Schwann cell derived tumors comprising schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs) are the most common cancers of the peripheral nervous system and often arise in patients with neurofibromatosis type-1 (NF-1) or type-2 (NF-2). NF-1 is caused by loss of NF1, a negative regulator of Ras signaling, and NF-2 is caused by loss of NF2, a pleiotropic tumor suppressor with numerous functions including inhibition of PAK signaling. However, whether functional interactions exist between the NF1 and NF2 tumor suppressors remain unclear. More broadly, there are currently no effective molecular therapies for patients with Schwann cell tumors beyond the MEK inhibitor selumetinib to treat neurofibromas in patients with NF-1. Here, we integrate DNA methylation profiling, whole exome sequencing, bulk and single-cell RNA sequencing, biochemistry, and pharmacology across human samples, cell lines, and mouse xenografts to identify cellular de-differentiation as a driver of malignant transformation and selumetinib resistance. Single nuclear RNA-sequencing of human neurofibromas (n = 3) or MPNSTs (n = 3) revealed a total of 13 cell types with increased proliferating, de-differentiated tumor cell populations in MPNST samples. Single cell RNA-sequencing of MPNST mouse xenografts revealed persistence of de-differentiated cell populations in selumetinib treated samples compared to vehicle control, suggesting cellular de-differentiation underlies treatment resistance. A genome-wide CRISPRi screen for mediators of selumetinib response in NF1 deficient neurofibroma cells revealed NF2 loss drives selumetinib resistance. Consistently, NF2 suppression in NF1 deficient neurofibroma cells caused Schwann cell de-differentiation and activation of PAK, a serine threonine kinase. Translationally, a small molecule PAK inhibitor in combination with selumetinib formed an effective therapy in mouse MPNST xenografts. In sum, we elucidate a paradigm of de-differentiation driving malignant transformation and treatment resistance in Schwann cell tumors, uncovering a functional link between the NF1 and NF2 tumor suppressors that sheds light on a novel therapeutic vulnerability.
EXTH-01. INTRATHECAL DELIVERY OF DENDRITIC CELL VACCINE ERADICATES TUMOR GROWTH AND PROTECTS AGAINST LEPTOMENINGEAL DISEASE RE-INOCULATION IN HER2+ AND TRIPLE NEGATIVE BREAST CANCER LMD XENOGRAFT MODELS
Authors: Vincent Law, Krithika Kodomudi, Colin Snyder, Peter Forsyth, Brian Czerniecki
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Leptomeningeal disease (LMD) occurs in approximately 5% of patients with breast cancer and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in breast cancer patients. In pre-clinical and clinical trials, the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ breast cancer patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in breast cancer-associated LMD immunocompetent animal models. METHODS Luciferase-labeled HER2+ TUBO breast cancer cells were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir in patients) for the IT administration of DCVs into the CSF. RESULTS AND DISCUSSION breast cancer-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p&amp;lt; 0.001). Interestingly, HER2-/HER3-DCV IT was able to rescue disease mice (71% in HER2+ breast cancer-LMD and 28% in triple negative breast cancer-LMD) and showed complete tumor regression. Some surviving mice were immune to subsequent tumor rechallenge. In mice CSF, we found evidence of CD4+ and CD8+ T-cells infiltration, and robust IFN-g and IL18 response upon DCV treatment. CONCLUSIONS Our preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in breast cancer patients with LMD.
PATH-43. HISTOLOGY OF RADIATION-INDUCED PSEUDOPROGRESSION WITH MULTIPLE FOCI IN TREATED GLIOBLASTOMA
Authors: Somdeb Banerjee, Di Tran, Christopher Trevino
Journal: Neuro-Oncology (2022)

Abstract Radiation induced pseudoprogression (PsP) of brain tumors is defined radiologically as new or enlarging areas of non-tumor magnetic resonance imaging (MRI) contrast enhancement developing within the initial 3-6 months after completing radiation. Distinguishing PsP from genuine tumor progression is of the utmost importance in deciding the clinical course of a patient. Although it is typically diagnosed radiologically, obtaining tissue histopathology can clarify diagnostic uncertainty. However, there is no consensus on defining PsP pathologically. We present the case of a 38-year-old man with a glioblastoma, IDH-wild type, CNS WHO Grade 4 (MGMT promoter methylated) with steroid-refractory PsP, and correlate both radiologic and pathologic features. After initial treatment with a gross total resection and radiation with concurrent temozolomide, he developed a new contrast-enhancing, mass-neutral enhancing lesion consistent with PsP, which did not resolve despite 4 cycles of temozolomide and prolonged steroid treatment. The enhancing lesion was resected, and the pathological examination demonstrated areas of non-pseudopallisading necrosis, numerous macrophages, astrocytosis, hyalinization of blood vessels, and low mitotic activity in the brain parenchyma with residual infiltrative glioma. These features were consistent with radiation-treatment effect and supported a diagnosis of PsP. Over time, varying definitions for PsP include a percentage threshold of treatment effect or necrosis per sample. However, the authors recognize potential sampling bias. Therefore, we recommend including treatment-related effects coupled with the absence of tumor proliferation in the results. These features include fibrinoid necrosis, hyalinization of blood vessels, and eosinophilic coagulation necrosis. From a therapeutic standpoint, it is important to comment on the presence or absence of residual glioma cell proliferation. This case highlights a unique paring of focal histopathology with correlative sections on MRI for pseudoprogression which has not been previously presented.
CNSC-17. GLIOMA SYNAPSES RECRUIT MECHANISMS OF ADAPTIVE PLASTICITY
Authors: Kathryn Taylor, Tara Barron, Helena Zhang, Alexa Hui, Griffin Hartmann, Lijun Ni, Humsa Venkatesh, Peter Du, Rebecca Mancusi, Belgin Yalçin, Isabelle Chau, Anitha Ponnuswami, Razina Aziz-Bose, Michelle Monje
Journal: Neuro-Oncology (2022)

Abstract The nervous system plays an increasingly appreciated role in the regulation of cancer. In malignant gliomas, neuronal activity drives tumor progression not only through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), but also through electrophysiologically functional neuron-to-glioma synapses. Malignant synapses are mediated by calcium-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in both pediatric and adult high-grade gliomas, and consequent depolarization of the glioma cell membrane drives tumor proliferation. The nervous system exhibits plasticity of both synaptic connectivity and synaptic strength, contributing to neural circuit form and functions. In health, one factor that promotes plasticity of synaptic connectivity and strength is activity-regulated secretion of the neurotrophin BDNF. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF-TrkB (tropomyosin receptor kinase B) signaling. Signaling through the receptor TrkB, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with the long-term potentiation (LTP) that is thought to contribute to memory and learning in the healthy brain. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells exerts growth inhibitory effects in vivo and in neuron:glioma co-cultures that cannot be explained by classical growth factor signaling alone. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression. While targeting Trk signaling is presently being explored for NTRK-fusion brain tumors, these findings indicate that BDNF-TrkB signaling may also represent an important therapeutic target for NTRK2 wildtype gliomas.
NIMG-55. A COMPARISON OF THREE DIFFERENT DEEP LEARNING-BASED MODELS TO PREDICT THE MGMT PROMOTER METHYLATION STATUS IN GLIOBLASTOMA USING BRAIN MRI
Authors: Shahriar Faghani, Bardia Khosravi, Mana Moassefi, Gian Marco Conte, Bradley Erickson
Journal: Neuro-Oncology (2022)

Abstract GBM is the most common primary malignant brain tumor in adults. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status is an important prognostic biomarker that predicts the response to temozolomide and guides the treatment decisions. At present, the only reliable way to determine MGMT promoter methylation status is through the analysis of tumor tissues. Given the limitations and complications of histology-based methods, an imaging-based approach for non-invasively MGMT promoter methylation status prediction is beneficial. This study aimed to develop and compare three different deep-learning-based approaches for predicting MGMT promoter methylation status non-invasively. We obtained 576 T2 weighted images (T2WIs) with their corresponding tumor masks and MGMT promoter methylation status from, The Brain Tumor Segmentation (BraTS) 2021 datasets. Dataset was split into five folds at the patient's level stratified by MGMT promoter methylation status to perform a 5-fold cross-validation. We developed three different models: voxel-wise, slice-wise, and whole-brain. For voxel-wise classification, methylated and unmethylated MGMT tumor masks were made into 1 and 2 with 0 background, respectively. We converted each T2WI into 32x32x32 patches. We trained a 3D-Vnet model for tumor segmentation. After inference, we constructed the whole brain volume based on the patch's coordinates. The final prediction of MGMT methylation status was made by majority voting between the predicted voxel values of the biggest connected component. For slice-wise classification, we trained an object detection model for tumor detection and MGMT methylation status prediction; then, we used majority voting for the final prediction. For the whole-brain approach, we trained a 3D Densenet121 for prediction. Whole-brain, slice-wise, voxel-wise, accuracy was 65.42%(SD 3.97%), 61.37%(SD 1.48%), and 56.84%(SD 4.38%) respectively. We found that across the whole-brain, slice-wise, and voxel-wise deep learning approaches, the whole-brain approach is the most effective approach for MGMT methylation status prediction on the BraTS 2021 dataset.